*2.2.2.1 Pigmented Epitelium Derived Factor (PEDF) decrease and retinal neurodegeneration*

PEDF is a trophic factor expressed by a multitude of retinal cells, an antagonist of VEGF. It decreases vascular permeability and plays an antioxidant role, protecting retinal cells from ROS. In the experimental setting, PEDF is decreased in aqueous and vitreous humor, early in preclinical stages of DR. The pathogenic mechanisms are supposed to be related with decreased insulin, as well as increased toxic mediators, such as glutamate. These early changes may induce mild changes in color vision, contrast sensitivity, visual field and electroretinogram oscillatory potentials [56–60].

**Figure 1.** *Pathogenesis of diabetic retinopathy.*

All these molecular mechanisms may lead to:


The first areas affected by thrombosis and ischemia are in the middle retinal periphery, and the answer is to release a range of mediators, of which the key role is played by VEGF, which promotes retinal neovascularization and interruption of blood flow in many areas (optical disc, macula, iridocorneal angle and iris). The response to retinal hypoperfusion, a maladaptive protective mechanism, leads to the appearance of fragile new vessels, prone to repeated bleeding and leakage, ultimately destroying normal retinal architecture (**Figure 1**).
